**4. Anatomy and pathophysiology**

#### **4.1. Anatomy**

A thorough understanding of anatomy is crucial to understanding Dupuytren's disease and its progression. Dupuytren's disease is a fibroproliferative disorder affecting the palmar aponeurosis, one of the three zones within the palmar fascial complex. The subcutaneous palmar aponeurosis is a continuation of the palmaris longus tendon, extending superficially to the palmaris brevis muscle and into the palmar surface. The palmar aponeurosis can be divided into three layers according to orientation: longitudinal, vertical, and transverse. The longitudinal fibers extend to the phalanges where they bifurcate and terminate as three separate insertions. The superficial layer inserts into the dermis and the deep layer inserts into the flexor and extensor mechanisms. The middle layer of the longitudinal fibers travel vertically next to the metacarpophalangeal (MCP) joint capsule forming spiral bands. Vertical fibers of the palmar aponeurosis include the superficial Grapow fibers, which anchor the skin to the aponeurosis, and the septa of Legueu and Juvara, which create fibro-osseous compartments to allow passage of flexor tendons, neurovascular bundles, and lumbrical muscles. Transverse fibers of the palmar aponeurosis include the transverse ligament and the natatory ligament.

allowing them to contract and draw tissue together. These muscle-like fibers align in the direction of stress [38, 39]. The residual phase is characterized by the disappearance of a nodule, and appearance of cords. The acellular cord causes shortening of the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joint and producing the classic contracted appearance of Dupuytren's disease. In the late phase, there is commonly impaired range of motion of the effected digit, and nerve damage and vascular insufficiency can occasionally be seen.

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Myofibroblasts are contractile cells that are α-smooth muscle actin positive and contribute to the contracture present in Dupuytren's disease. During the early phase of disease, myofibroblasts become densely packed in the palmar aponeurosis and produce an increased type 3/type 1 collagen ratio. The accumulation of fibroblasts and type III collagen creates the characteristic early nodule. This abundant type 3 collagen production is similar to connective tissue scar formation, and may or may not contribute to the pathophysiology of Dupuytren's disease [40]. The source of myofibroblasts in Dupuytren's disease remains unclear. Some argue that the fibroblast-myofibroblasts transformation is induced by local ischemia and hypoxia.

Biochemical changes to the palmar fascia may contribute to the development of Dupuytren's disease. These changes include increased glycosaminoglycan content, increased hydroxylysine content, and increased reducible crosslinks found in affected palmar aponeuroses [40]. Myofibroblasts found in the palmar fascia produce fibronectin, a glycoprotein thought to encourage cell-cell and cell-extracellular matrix adherence [41, 42]. This contributes to the thickening of the palmar fascia seen in the disease. Dermatan sulfate has been found to be two fold greater in tissue affecting by Dupuytren's and is known to affect collagen organization, deposition rate, and maintenance of fibers [43]. The same study also demonstrated an increased heparin sulfate composition in patients with Dupuytren's, which has been shown to play a role in cell recognition, adhesion, growth control, and angiogenesis. Research has also shown a change in the architecture of the palmar fascia in Dupuytren's patients. Compared to normal fascia, fascia in Dupuytren's patients has more hydroxyl-lysino-hydroxy-norleucine crosslinking which was absent in normal tissue [44, 45]. It is unclear how this increased cross-

Many studies have pointed to the role of growth factors and cytokines in the pathogenesis of Dupuytren's disease. An increased production of IL-1α and IL-1β is seen in Dupuytren's palmar fascia. <sup>62</sup> These cytokines are involved in proinflammatory processes including local fibroblast proliferation, which can potentially contribute to the active stage of Dupuytren's disease [46]. There is also an increase in bFGF which contributes to fibroblast growth and proliferation, and increased TGF-β, which contributes to collagen synthesis and fibroblast chemotaxis [46]. The study concluded that increased release of cytokines and growth factors relative to normal reparative tissue may suggest a locally driven fibroblast proliferation contributing

*4.2.1. Myofibroblasts*

*4.2.2. Biochemical changes*

linking component contributes to the severity of disease.

*4.2.3. Cytokines and prostaglandins*

Dupuytren's disease is characterized by the transformation of normal, palmar fascial bands into fibrotic, contracted tissue called cords. Different manifestations and stages of the disease are dependent on the anatomical bands that are affected. Early disease often affects the superficial Grapow fibers, forming thickened skin in the affected area. Pretendinous cords are the most common and result in skin dimpling and MCP contracture. The spiral cord consists of the middle pretendinous band, spiral band, lateral digital sheet, and Grayson ligament result in MCP and proximal interphalangeal (PIP) contracture and can also be accompanied with a medially displaced neurovascular bundle [36]. Other cords that can form include the central and lateral cords which can lead to a combination of PIP or distal inter-phalangeal (DIP) contractures while natatory cords can lead to web space contractures.

#### **4.2. Pathophysiology**

The pathophysiology of Dupuytren's is similar to the normal connective tissue healing process. However, there are aspects of the Dupuytren's process that differ and contribute to its pathogenesis. In Dupuytren's there is an increased number of myofibroblasts producing type 3 collagen, a change in biochemical composition of the fascia, as well as an abundance of cytokines and prostaglandins contribute to the pathogenesis. An immune mediated component of the disease has also been proposed and researched. Luck et al. describes three distinct microscopic phases of Dupuytren's disease [37]. The first stage is called the proliferative phase, and is characterized by increased fibroblast presence and proliferation in fascial bands, forming a nodule. On a cellular level, these nodules represent the accumulation of myofibroblasts, collagen, and extracellular matrix components within the palmar fascia, resulting in fibrotic, adherent lesions that decrease mobility of the joint. In this stage, there can be as high as a fortyfold increase in the amount of proliferating fibroblasts [38]. The active or "involutional" phase is dominated by myofibroblasts, which contain myofibrillar bundles in the cytoplasm, allowing them to contract and draw tissue together. These muscle-like fibers align in the direction of stress [38, 39]. The residual phase is characterized by the disappearance of a nodule, and appearance of cords. The acellular cord causes shortening of the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joint and producing the classic contracted appearance of Dupuytren's disease. In the late phase, there is commonly impaired range of motion of the effected digit, and nerve damage and vascular insufficiency can occasionally be seen.

#### *4.2.1. Myofibroblasts*

**4. Anatomy and pathophysiology**

A thorough understanding of anatomy is crucial to understanding Dupuytren's disease and its progression. Dupuytren's disease is a fibroproliferative disorder affecting the palmar aponeurosis, one of the three zones within the palmar fascial complex. The subcutaneous palmar aponeurosis is a continuation of the palmaris longus tendon, extending superficially to the palmaris brevis muscle and into the palmar surface. The palmar aponeurosis can be divided into three layers according to orientation: longitudinal, vertical, and transverse. The longitudinal fibers extend to the phalanges where they bifurcate and terminate as three separate insertions. The superficial layer inserts into the dermis and the deep layer inserts into the flexor and extensor mechanisms. The middle layer of the longitudinal fibers travel vertically next to the metacarpophalangeal (MCP) joint capsule forming spiral bands. Vertical fibers of the palmar aponeurosis include the superficial Grapow fibers, which anchor the skin to the aponeurosis, and the septa of Legueu and Juvara, which create fibro-osseous compartments to allow passage of flexor tendons, neurovascular bundles, and lumbrical muscles. Transverse fibers of the palmar aponeurosis include the transverse ligament and the natatory ligament. Dupuytren's disease is characterized by the transformation of normal, palmar fascial bands into fibrotic, contracted tissue called cords. Different manifestations and stages of the disease are dependent on the anatomical bands that are affected. Early disease often affects the superficial Grapow fibers, forming thickened skin in the affected area. Pretendinous cords are the most common and result in skin dimpling and MCP contracture. The spiral cord consists of the middle pretendinous band, spiral band, lateral digital sheet, and Grayson ligament result in MCP and proximal interphalangeal (PIP) contracture and can also be accompanied with a medially displaced neurovascular bundle [36]. Other cords that can form include the central and lateral cords which can lead to a combination of PIP or distal inter-phalangeal (DIP) con-

tractures while natatory cords can lead to web space contractures.

The pathophysiology of Dupuytren's is similar to the normal connective tissue healing process. However, there are aspects of the Dupuytren's process that differ and contribute to its pathogenesis. In Dupuytren's there is an increased number of myofibroblasts producing type 3 collagen, a change in biochemical composition of the fascia, as well as an abundance of cytokines and prostaglandins contribute to the pathogenesis. An immune mediated component of the disease has also been proposed and researched. Luck et al. describes three distinct microscopic phases of Dupuytren's disease [37]. The first stage is called the proliferative phase, and is characterized by increased fibroblast presence and proliferation in fascial bands, forming a nodule. On a cellular level, these nodules represent the accumulation of myofibroblasts, collagen, and extracellular matrix components within the palmar fascia, resulting in fibrotic, adherent lesions that decrease mobility of the joint. In this stage, there can be as high as a fortyfold increase in the amount of proliferating fibroblasts [38]. The active or "involutional" phase is dominated by myofibroblasts, which contain myofibrillar bundles in the cytoplasm,

**4.1. Anatomy**

62 Essentials of Hand Surgery

**4.2. Pathophysiology**

Myofibroblasts are contractile cells that are α-smooth muscle actin positive and contribute to the contracture present in Dupuytren's disease. During the early phase of disease, myofibroblasts become densely packed in the palmar aponeurosis and produce an increased type 3/type 1 collagen ratio. The accumulation of fibroblasts and type III collagen creates the characteristic early nodule. This abundant type 3 collagen production is similar to connective tissue scar formation, and may or may not contribute to the pathophysiology of Dupuytren's disease [40]. The source of myofibroblasts in Dupuytren's disease remains unclear. Some argue that the fibroblast-myofibroblasts transformation is induced by local ischemia and hypoxia.

#### *4.2.2. Biochemical changes*

Biochemical changes to the palmar fascia may contribute to the development of Dupuytren's disease. These changes include increased glycosaminoglycan content, increased hydroxylysine content, and increased reducible crosslinks found in affected palmar aponeuroses [40]. Myofibroblasts found in the palmar fascia produce fibronectin, a glycoprotein thought to encourage cell-cell and cell-extracellular matrix adherence [41, 42]. This contributes to the thickening of the palmar fascia seen in the disease. Dermatan sulfate has been found to be two fold greater in tissue affecting by Dupuytren's and is known to affect collagen organization, deposition rate, and maintenance of fibers [43]. The same study also demonstrated an increased heparin sulfate composition in patients with Dupuytren's, which has been shown to play a role in cell recognition, adhesion, growth control, and angiogenesis. Research has also shown a change in the architecture of the palmar fascia in Dupuytren's patients. Compared to normal fascia, fascia in Dupuytren's patients has more hydroxyl-lysino-hydroxy-norleucine crosslinking which was absent in normal tissue [44, 45]. It is unclear how this increased crosslinking component contributes to the severity of disease.

#### *4.2.3. Cytokines and prostaglandins*

Many studies have pointed to the role of growth factors and cytokines in the pathogenesis of Dupuytren's disease. An increased production of IL-1α and IL-1β is seen in Dupuytren's palmar fascia. <sup>62</sup> These cytokines are involved in proinflammatory processes including local fibroblast proliferation, which can potentially contribute to the active stage of Dupuytren's disease [46]. There is also an increase in bFGF which contributes to fibroblast growth and proliferation, and increased TGF-β, which contributes to collagen synthesis and fibroblast chemotaxis [46]. The study concluded that increased release of cytokines and growth factors relative to normal reparative tissue may suggest a locally driven fibroblast proliferation contributing to the development of Dupuytren's disease. Research has also demonstrated prostaglandins PGE2 and PGF2α play a role in contractility of smooth muscle associated with myofibroblasts [44, 47]. This contractile influence on myofibroblasts is thought to contribute to the contraction of tissue late in the disease. The source of these prostaglandins are possibly from microcirculation and perinodular fat, as nodules are highly vascularized and fatty.

dimpling of the skin around the effected joint. The underlying fat on the medial palm becomes fibrotic near the distal palmar crease. Active range of motion (ROM) and strength testing in early disease will reveal no limitations, though more severe skin adhesions can lead to a slight

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The appearance of Dupuytren's nodules and cords signifies the intermediate phase of disease. Nodule formation is often one of the first patient complaints and occurs during intermediate stages of the disease. Approximately 42% of patients with Dupuytren's disease present to the office due to a nodule [12]. Nodules most commonly form proximal to the palmar crease overlying the metacarpophalangeal joint of the affected digit, and encompass the superficial layers of the palmar and digital fascia. Sometimes digital nodules are seen at the base of the proximal interphalangeal joint. Though often painless, larger nodules can cause pain when they exert pressure on underlying flexor tendons. Painful, chronic nodules are more indicative of intrinsic joint disease and rheumatoid arthritis, and must be differentiated from a Dupuytren's disease nodule. After the appearance of a nodule, a pathologic cord may form within the palmar fascia. Approximately 12% of patients seek will seek care following development of a cord [12]. Nodules often regresses, but in some cases can be present simultaneously with Dupuytren's cords. Initial cords are often unnoticeable and blend in with the underlying connective tissue, but over time, they become thick and resemble subcutaneous tendon-like structures upon inspection (**Figure 1**). Palpation reveals an immobile, thickened cord. Cord formation is extremely variable in terms of location. The most common cords arise in the palm, and include peritendinous, natatory, and vertical cords arising from their respective bands in the palmar

**Figure 1.** A patient with Dupuytren's cords leading to contractures and affecting the bilateral small and ring fingers.

decrease in mobility and function of the affected digits in some patients.

**5.2. Intermediate phase**

#### *4.2.4. Immune mediated*

Studies have suggested an immune mediated response in the pathophysiology of Dupuytren's disease. Mayerl et al. describe abundant accumulation of immune cells in Dupuytren's tissue, including mononuclear CD3+, CD4+ > CD8+, and primarily a Th1 mediated response [39]. These clusters of immune cells were found around blood vessels in the area, suggesting the fibroproliferation exists in Dupuytren's may be due to microvascular damage mediated by the immune system. Further research is required to determine the relationship of Dupuytren's to an immune mediated response.
